Jérémy Morille1, Marion Mandon1, Stéphane Rodriguez1, David Roulois1, Simon Leonard1, Alexandra Garcia1, Sandrine Wiertlewski1, Emmanuelle Le Page1, Laureline Berthelot1, Arnaud Nicot1, Camille Mathé1, Flora Lejeune1, Karin Tarte1, Céline Delaloy1, Patricia Amé1, David Laplaud1, Laure Michel2. 1. From the Université de Nantes (J.M., A.G., L.B., A.N., C.M., F.L., D.L.), INSERM, CR2TI, UMR1064, Nantes; Pôle Biologie (M.M., K.T., P.A., L.M.), Laboratoire SITI, University Hospital; INSERM UMR1236 MicrOenvironment and B-Cell: Immunopathology Cell Differentiation and Cancer (M.M., S.R., D.R., S.L., K.T., C.D., P.A., L.M.), Univ Rennes, Etablissement Français du Sang Bretagne, Rennes; LabEx IGO "Immunotherapy (S.L.), Graft, Oncology", Nantes; Service de neurologie (S.W., F.L., D.L.), CRC-SEP Pays de La Loire and CIC 1314, CHU Nantes; Neurology Department (E.L.P., L.M.), Rennes University Hospital; and Clinical Neuroscience Centre (E.L.P., L.M.), CIC_P1414 INSERM, Rennes, University Hospital, Rennes University. 2. From the Université de Nantes (J.M., A.G., L.B., A.N., C.M., F.L., D.L.), INSERM, CR2TI, UMR1064, Nantes; Pôle Biologie (M.M., K.T., P.A., L.M.), Laboratoire SITI, University Hospital; INSERM UMR1236 MicrOenvironment and B-Cell: Immunopathology Cell Differentiation and Cancer (M.M., S.R., D.R., S.L., K.T., C.D., P.A., L.M.), Univ Rennes, Etablissement Français du Sang Bretagne, Rennes; LabEx IGO "Immunotherapy (S.L.), Graft, Oncology", Nantes; Service de neurologie (S.W., F.L., D.L.), CRC-SEP Pays de La Loire and CIC 1314, CHU Nantes; Neurology Department (E.L.P., L.M.), Rennes University Hospital; and Clinical Neuroscience Centre (E.L.P., L.M.), CIC_P1414 INSERM, Rennes, University Hospital, Rennes University. laure.michel@chu-rennes.fr.
Abstract
BACKGROUND AND OBJECTIVES: Tertiary lymphoid structures and aggregates are reported in the meninges of patients with multiple sclerosis (MS), especially at the progressive stage, and are strongly associated with cortical lesions and disability. Besides B cells, these structures comprise follicular helper T (Tfh) cells that are crucial to support B-cell differentiation. Tfh cells play a pivotal role in amplifying autoreactive B cells and promoting autoantibody production in several autoimmune diseases, but very few are known in MS. In this study, we examined the phenotype, frequency, and transcriptome of circulating cTfh cells in the blood and CSF of patients with relapsing-remitting MS (RRMS). METHODS: The phenotype and frequency of cTfh cells were analyzed in the blood of 39 healthy controls and 41 untreated patients with RRMS and in the CSF and paired blood of 10 patients with drug-naive RRMS at diagnosis by flow cytometry. Using an in vitro model of blood-brain barrier, we assessed the transendothelial migratory abilities of the different cTfh-cell subsets. Finally, we performed an RNA sequencing analysis of paired CSF cTfh cells and blood cTfh cells in 8 patients sampled at their first demyelinating event. RESULTS: The blood phenotype and frequency of cTfh cells were not significantly modified in patients with RRMS. In the CSF, we found an important infiltration of Tfh1 cells, with a high proportion of activated PD1+ cells. We demonstrated that the specific subset of Tfh1 cells presents increased migration abilities to cross an in vitro model of blood-brain barrier. Of interest, even at the first demyelinating event, cTfh cells in the CSF display specific characteristics with upregulation of EOMES gene and proinflammatory/cytotoxic transcriptomic signature able to efficiently distinguish cTfh cells from the CSF and blood. Finally, interactome analysis revealed potential strong cross talk between pathogenic B cells and CSF cTfh cells, pointing out the CSF as opportune supportive compartment and highlighting the very early implication of B-cell helper T cells in MS pathogenesis. DISCUSSION: Overall, CSF enrichment in activated Tfh1 as soon as disease diagnosis, associated with high expression of EOMES, and a predicted high propensity to interact with CSF B cells suggest that these cells probably contribute to disease onset and/or activity.
BACKGROUND AND OBJECTIVES: Tertiary lymphoid structures and aggregates are reported in the meninges of patients with multiple sclerosis (MS), especially at the progressive stage, and are strongly associated with cortical lesions and disability. Besides B cells, these structures comprise follicular helper T (Tfh) cells that are crucial to support B-cell differentiation. Tfh cells play a pivotal role in amplifying autoreactive B cells and promoting autoantibody production in several autoimmune diseases, but very few are known in MS. In this study, we examined the phenotype, frequency, and transcriptome of circulating cTfh cells in the blood and CSF of patients with relapsing-remitting MS (RRMS). METHODS: The phenotype and frequency of cTfh cells were analyzed in the blood of 39 healthy controls and 41 untreated patients with RRMS and in the CSF and paired blood of 10 patients with drug-naive RRMS at diagnosis by flow cytometry. Using an in vitro model of blood-brain barrier, we assessed the transendothelial migratory abilities of the different cTfh-cell subsets. Finally, we performed an RNA sequencing analysis of paired CSF cTfh cells and blood cTfh cells in 8 patients sampled at their first demyelinating event. RESULTS: The blood phenotype and frequency of cTfh cells were not significantly modified in patients with RRMS. In the CSF, we found an important infiltration of Tfh1 cells, with a high proportion of activated PD1+ cells. We demonstrated that the specific subset of Tfh1 cells presents increased migration abilities to cross an in vitro model of blood-brain barrier. Of interest, even at the first demyelinating event, cTfh cells in the CSF display specific characteristics with upregulation of EOMES gene and proinflammatory/cytotoxic transcriptomic signature able to efficiently distinguish cTfh cells from the CSF and blood. Finally, interactome analysis revealed potential strong cross talk between pathogenic B cells and CSF cTfh cells, pointing out the CSF as opportune supportive compartment and highlighting the very early implication of B-cell helper T cells in MS pathogenesis. DISCUSSION: Overall, CSF enrichment in activated Tfh1 as soon as disease diagnosis, associated with high expression of EOMES, and a predicted high propensity to interact with CSF B cells suggest that these cells probably contribute to disease onset and/or activity.
Authors: Tim Stuart; Andrew Butler; Paul Hoffman; Christoph Hafemeister; Efthymia Papalexi; William M Mauck; Yuhan Hao; Marlon Stoeckius; Peter Smibert; Rahul Satija Journal: Cell Date: 2019-06-06 Impact factor: 41.582
Authors: Baerbel Keller; Valentina Strohmeier; Ina Harder; Susanne Unger; Kathryn J Payne; Geoffroy Andrieux; Melanie Boerries; Peter Tobias Felixberger; Jonathan J M Landry; Alexandra Nieters; Anne Rensing-Ehl; Ulrich Salzer; Natalie Frede; Susanne Usadel; Roland Elling; Carsten Speckmann; Ina Hainmann; Elizabeth Ralph; Kimberly Gilmour; Marjolein W J Wentink; Mirjam van der Burg; Hye Sun Kuehn; Sergio D Rosenzweig; Uwe Kölsch; Horst von Bernuth; Petra Kaiser-Labusch; Florian Gothe; Sophie Hambleton; Alexandru Daniel Vlagea; Ana Garcia Garcia; Laia Alsina; Gašper Markelj; Tadej Avcin; Julia Vasconcelos; Margarida Guedes; Jing-Ya Ding; Cheng-Lung Ku; Bella Shadur; Danielle T Avery; Nils Venhoff; Jens Thiel; Heiko Becker; Lucía Erazo-Borrás; Claudia Milena Trujillo-Vargas; José Luis Franco; Claire Fieschi; Satoshi Okada; Paul E Gray; Gulbu Uzel; Jean-Laurent Casanova; Manfred Fliegauf; Bodo Grimbacher; Hermann Eibel; Stephan Ehl; Reinhard E Voll; Marta Rizzi; Polina Stepensky; Vladimir Benes; Cindy S Ma; Claudia Bossen; Stuart G Tangye; Klaus Warnatz Journal: Sci Immunol Date: 2021-10-08
Authors: Stephen L Hauser; Emmanuelle Waubant; Douglas L Arnold; Timothy Vollmer; Jack Antel; Robert J Fox; Amit Bar-Or; Michael Panzara; Neena Sarkar; Sunil Agarwal; Annette Langer-Gould; Craig H Smith Journal: N Engl J Med Date: 2008-02-14 Impact factor: 91.245
Authors: Laura Couloume; Juliette Ferrant; Simon Le Gallou; Marion Mandon; Rachel Jean; Nadège Bescher; Helene Zephir; Gilles Edan; Eric Thouvenot; Aurelie Ruet; Marc Debouverie; Karin Tarte; Patricia Amé; Mikael Roussel; Laure Michel Journal: Front Immunol Date: 2021-05-04 Impact factor: 7.561
Authors: Yingyao Zhou; Bin Zhou; Lars Pache; Max Chang; Alireza Hadj Khodabakhshi; Olga Tanaseichuk; Christopher Benner; Sumit K Chanda Journal: Nat Commun Date: 2019-04-03 Impact factor: 14.919
Authors: Luisa Bell; Alexander Lenhart; Andreas Rosenwald; Camelia M Monoranu; Friederike Berberich-Siebelt Journal: Front Immunol Date: 2020-01-15 Impact factor: 7.561
Authors: Akshaya Ramesh; Ryan D Schubert; Ariele L Greenfield; Ravi Dandekar; Rita Loudermilk; Joseph J Sabatino; Matthew T Koelzer; Edwina B Tran; Kanishka Koshal; Kicheol Kim; Anne-Katrin Pröbstel; Debarko Banerji; Chu-Yueh Guo; Ari J Green; Riley M Bove; Joseph L DeRisi; Jeffrey M Gelfand; Bruce A C Cree; Scott S Zamvil; Sergio E Baranzini; Stephen L Hauser; Michael R Wilson Journal: Proc Natl Acad Sci U S A Date: 2020-08-28 Impact factor: 11.205